SLC16A1/MCT1 和 SLC16A3/MCT4 参与肝细胞癌细胞系中 l-乳酸的转运,Biopharmaceutics & Drug Disposition

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SLC16A1/MCT1 和 SLC16A3/MCT4 参与肝细胞癌细胞系中 l-乳酸的转运
Biopharmaceutics & Drug Disposition ( IF 1.7 ) Pub Date : 2022-09-14 , DOI: 10.1002/bdd.2329
Yuto Mukai ₁ , Atsushi Yamaguchi ₂ , Tomoya Sakuma ₁ , Takanobu Nadai ₁ , Ayako Furugen ₁ , Katsuya Narumi ₁ , Masaki Kobayashi ₁

Affiliation

已经报道了十四种单羧酸转运蛋白 (MCT) 的异构体。在 MCT 异构体中，MCT1、MCT2 和MCT4在 L-乳酸/质子协同转运中发挥作用，并参与细胞内能量和 pH 值的平衡。因此，MCT1、MCT2 和 MCT4 与正常和病理细胞的能量代谢过程有关。在本研究中，我们评估了 MCT1、MCT2 和 MCT4 的表达以及这三种 MCT 同种型对肝细胞癌 (HCC) 细胞中l-乳酸摄取的贡献。在 HepG2 和 Huh-7 细胞中，L-乳酸转运是 pH 依赖性的，这是 MCT1、MCT2 和 MCT4 的特征。此外，升在 HepG2 和 Huh-7 细胞中，MCT1 和 MCT4 抑制剂选择性地抑制了乳酸摄取。HepG2 细胞的动力学分析表明L-乳酸摄取是双相的。虽然HepG2细胞中MCT1和MCT4的敲低降低了l-乳酸的摄取，但MCT2的敲低对l-乳酸的摄取没有影响。因此，我们得出结论，MCT1 和 MCT4 在 pH 6.0 时都参与了HepG2 和 Huh-7 细胞中l-乳酸的转运。相比之下，PXB 细胞，即从人源化小鼠肝脏中新鲜分离的肝细胞，与 HCC 细胞系相比，在 pH 6.0 时表现出较低的 MCT4 表达和 L-乳酸摄取。总之，MCT4 有助于lHCC 细胞中的乳酸转运与正常肝细胞相比在 HCC 中存在显着差异，并且具有作为 HCC 治疗靶点的潜力。

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Involvement of SLC16A1/MCT1 and SLC16A3/MCT4 in l-lactate transport in the hepatocellular carcinoma cell line

Fourteen isoforms of the monocarboxylate transporter (MCT) have been reported. Among the MCT isoforms, MCT1, MCT2, and MCT4 play a role in l-lactate/proton cotransport and are involved in the balance of intracellular energy and pH. Therefore, MCT1, MCT2, and MCT4 are associated with energy metabolism processes in normal and pathological cells. In the present study, we evaluated the expression of MCT1, MCT2, and MCT4 and the contribution of these three MCT isoforms to l-lactate uptake in hepatocellular carcinoma (HCC) cells. In HepG2 and Huh-7 cells, l-lactate transport was pH-dependent, which is characteristic of MCT1, MCT2, and MCT4. Furthermore, l-lactate uptake was selectively inhibited by MCT1 and MCT4 inhibitors in HepG2 and Huh-7 cells. Kinetic analysis of HepG2 cells demonstrated that l-lactate uptake was biphasic. Although the knockdown of MCT1 and MCT4 in the HepG2 cells decreased the uptake of l-lactate, the knockdown of MCT2 had no effect on the uptake of l-lactate. Consequently, we concluded that both MCT1 and MCT4 were involved in the transport of l-lactate in HepG2 and Huh-7 cells at pH 6.0. In contrast, PXB-cells, freshly isolated hepatocytes from humanized mouse livers, showed lower MCT4 expression and l-lactate uptake at pH 6.0 compared to that in HCC cell lines. In conclusion, MCT4, which contributes to l-lactate transport in HCC cells, is significantly different in HCC compared to normal hepatocytes, and has potential as a target for HCC treatment.

更新日期：2022-09-14

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